1. Technical Field
This invention relates to synthetic processes for preparing dipeptide compounds possessing pharmacological activity, particularly as inhibitors of protease enzymes.
2. Background Information
Peptidyl nitrites have been reported as protease inhibitors. For example, both nitrites and ketoheterocycles are described by B. A. Rowe et al. (U.S. Pat. No. 5,714,471) as protease inhibitors useful in the treatment of neurodegenerative diseases. Peptidyl nitrites are reported by B. Malcolm et al. (WO 9222570) as inhibitors of picornavirus protease. B. J. Gour-Salin (Can. J. Chem., 1991, 69, 1288) and T. C. Liang (Arch. Biochim. Biophys., 1987, 252, 626) described peptidyl nitrites as inhibitors of papain
Examples of dipeptide nitrile-based cathepsin S inhibitors have been reported by Novartis application, WO 99/24460, 1999 and related U.S. Pat. No. 6,353,017. One of the generic structures is depicted below.

The processes provided therein provide for converting amides such as
to the corresponding nitrites and several condensation reactions of intermediates to arrive at (I). The disadvantages of these methods are a linear sequence and deprotection/acylation reations after a chiral center is established which has the potential problems of racemization
U.S. Pat. Nos. 6,525,052 and 6,420,364, U.S. provisional application Ser. No. 60/454,239 each commonly owned by the assignee of the present application, describe dipeptide nitrites bearing P1 heterocycles. One of the synthetic schemes shown in examples 2,3 and 5 discloses a process beginning with the preparation of intermediate 2-benzyloxycarbonylamino-5,5-dimethyl-heptanoic acid for use in the synthesis of particular peptide nitrites disclosed therein.